Patent EA-000464-B1 (EA)
Title: Cyclic peptide antifungal agents
Inventor: BORROMEO PETER S
IPC: A61K38/12
Filed: 1996-04-03
Abstract: 1. A compound of formula I:   wherein: R' is hydrogen, methyl or NH2C(O)CH2-; R" and R'" are independently methyl or hydrogen; R<x1>, R<x2>. R<y1>, R<y2>, R<y3>, and R<y4> are independently hydroxy or hydrogen; R0 is a group of the formula   R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, p-halo phenyl, p-nitrophenyl, phenoxy, benzyl, p-halo-benzyl, or p-nitrobenzyl; I) R2 is a group of the formula   where: A) R3 is C1-C12 alkyl, C1-C6 alkoxy or quinolyl; B) R3 is -O-CH2)m-[O-(CH2)n]p-O-(C1-C12 alkyl); m and n are independently 2, 3 or 4; p is 0 or 1; or C) R3 is -Y-(C1-C12 alkyl); Y is -C [triple bond] C- or -CH=CH-; or D) R3 is -0-(CH<2>)q-G; q is 2, 3 or 4; G is C7-C10 bicycloalkyl or C7-C14 tricycloalkyl; or II) R2 is a group of the formula   where: Z is -O-, -C [triple bond] C-, -CH=CH-, -CH2-CH2-, -CH2-, or a bond; A) R4 is hydrogen. C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl. C2-C12 alkynyl, C2-C12 substituted alkynyl, C1-C12 alkoxy, C3-C12 cycloalkyl, C7-C10 bicycloalkyl, C7-C14 tricycloalkyl. C3-C12 cycloalkoxy, naphthyl, pyridyl, thienyl, benzothienyl, quinolyl or phenyl; or B) R4 is phenyl substituted by amino. C1-C12 alkylthio, halo C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl C1-C12 substituted alkyl, C2-C12 substituted alkenyl, C2-C12 substituted alkynyl, C1-C12 alkoxy, trifluoromethyl, phenyl, substituted phenyl, or phenyl substituted with a group of the formula -O-(CH2)m-[O-(CH2)n]p-O- (C1-C12 alkyl) where m, n and p are as defined above; or C) R4 is C1-C12 alkoxy substituted with halo C3-C12 cycloalkyl, C7-C10 bicycioalkyl, C7-C14 tricycloalkyl, C1-C6 alkoxy, C2-C12 alkynyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, formamido, C2-C12 alkanoylamino, or phenyl substituted with a group of the formula -O-(CH2)m-[O-(CH2)n]p-O-(C1-C12 alkyl) where m, n and p are as defined above; or D) R4 is -O-(CH2)r-W-R5; r is 2, 3 or 4; W is pyrrolidino, piperidino or piperazino; R5 is hydrogen, C1-C12 alkyl, C3-C12 cycloalkyl, benzyl or C3-C12 cycloalkylmethyl; or E) R4 is -Y<1>-R6; Y<1> is -C [triple bond] C- or -CH=CH-; R6 is C3-C12 cycloalkyl, C7-C10 bicycloalkyl, C7-C14 tricycloalkyl, C3-C12 cycloalkenyl, naphthyl, benzothiazolyl, thienyl, indanyl, fluorenyl, or phenyl substituted with C1-C12 alkylthio, C2-C12 alkenyl, C2-C12 alkynyl, halo(C1-C6 alkoxy) or a group of the formula -O-(CH2)r-W-R5 where r, W and R5 are as defined above; or R6 is phenyl substituted with a group of the formula -O-(CH2)m-[O-(CH2)n]p-O-(C1-C12 alkyl) where m, n and p are as defined above; or F) R4 is C1-C12 alkoxy substituted with a group of the formula -NHC(O)R7; R7 is C1-C6 alkoxy, or phenyl(C1-C6 alkoxy); or III) R2 is a group of the formula   where R<8> is C1-C12 alkoxy or a group of the formula -O-(CH2)m-[O-(CH2)n]p-O-(C1-C12 alkyl) where m, n and p are as defined above; or IV) R2 is a group of the formula   where: Y and R6 are as defined above; R9 is phenyl, C1-C12 alkyl, or C1-C12 alkoxy; or V) R2 is naphthoyl substituted with R4 where R4 is as defined above; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1 where: R", R", and R'" are each methyl; R<y1>, R<y2>, Ry3, Ry4 are each hydroxy; R<xl> and R<x2> are hydrogen; or a pharmaceutically acceptable salt thereof. 3. A compound according to Claim 2 where: R2 is a group of the formula   where: Z is -C [triple bond] C- or a bond; A) R4 is hydrogen, C2-C12 alkynyl, C2-C12 substituted alkynyl, C1-C12 alkoxy, C3-C12 cycloalkoxy, or phenyl; or B) R4 is phenyl substituted by C1-C12 alkoxy, or a group of the formula -O-(CH2)2-O-(C1-C6 alkyl) ; or C) R4 is C1-C12 alkoxy substituted with C3-C12 cycloalkyl, C7-C14 tricycloalkyl, C7-C14 tricycloalkoxy, C1-C6 alkoxy, amino, di (C1-C4 alkyl)amino, formamido, or phenyl substituted with a group of the formula -O-(CH2)2-O" (C1-C6 alkyl); or D) R4 is -O-(CH2)r-W-R5; r is 2 or 3; W is piperidino; R5 is hydrogen, C1-C12 alkyl, C3~C12 cycloalkyl, benzyl or C3-C12 cycloalkylmethyl; or E) R4 is -Y<1>-R6; Y<1> is -C [triple bond] C-; R6 is phenyl substituted with C1-C12 alkylthio. C2-C12 alkenyl, C2-C12 alkynyl, halo(C1-C6 alkoxy); or R6 is phenyl substituted with a group of the formula -O-(CH2)r-W-R5 where r. W and R5 are as defined above; or R6 is phenyl substituted with a group of the formula -O-(CH2)2-O-(C1-C6 alkyl); F) R4 is C1-C12 alkoxy substituted with a group of the formula -NHC(O)R7; R7 is C1-C6 alkoxy, or phenyl (C1-C6 alkoxy) ; or a pharmaceutically acceptable salt thereof. 4. A compound according to Claim 3 where R1 is C1-C4 alkyl. C1-C4 alkoxy, phenyl, p-chloro-phenyl. p-bromo-phenyl. or p-nitro-phenyl, benzyl, p-chloro-benzyl, p-bromo-benzyl, or p-nitro-benzyl; or a pharmaceutically acceptable salt thereof. 5. A compound according to Claim 4 where R1 is methyl, ethyl, methoxy, ethoxy, phenyl, benzyl; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 5 where Z is a bond; R4 is phenyl substituted by n-pentoxy; and R1 is methyl; or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 6, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor. 8. A compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any of Claims 1 to 6 for use as a pharmaceutical. 9. A method of treating a fungal infection in a mammal which comprises administering to such a mammal a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 6. 10. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof as claimed in any of Claims 1 to 6, comprising reacting a compound of formula IC   where R', R", R'", R<x1>, R<x2>, R<y1> R<y2>, R<y3> R<y4> and R2 are as defined in Claim 1; with a substituted C1-C6 alkyl phosphoric acid, phenyl phosphoric acid, substituted C1-C6 alkyl phosphate or phenyl phosphate; followed, if desired, by forming a pharmaceutically acceptable salt thereof.